Organocatalytic Cascade Reactions for the Diversification of Thiopyrano‐Piperidone Fused Rings Utilizing Trienamine Activation

Abstract

An aminocatalytic privileged diversity‐oriented synthesis (ApDOS) strategy utilizing trienamine catalysis for the construction of diverse and complex thiopyrans‐piperidone fused rings through a thia‐Diels–Alder/nucleophilic ring‐closing sequence by using dithioamides as activated heterodienophiles is reported. Following this strategy, a super cascade reaction to assemble nine fused rings can be achieved by employing a bis‐dithioamide. Additionally, by linking an indole moiety on the dithioamide, a Pictet–Spengler type reaction can be promoted once the cascade sequence has been achieved, leading to more complex penta‐ hexa‐ and heptacyclic fused ring derivatives in a one‐pot process. This investigation opens new perspectives for the synthesis of a new class of complex and diverse thiopyrans that contribute to populate new relevant regions in the chemical space.

Anxiolytic-Like and Antidepressant Effects of a 13H-indolo[2,3-a]thiopyrano[2,3-g]quinolizine Derivative

“…We started our investigation with the synthesis of 4, prepared following our previously reported thio-Diels-Alder/nucleophilic ring-closing/Pictet-Spengler cascade methodology, utilizing an organocatalytic trienamine's activation [5] (Scheme 1) on a smaller scale (20 mg). With this slight modification, product 4 was obtained after flash column chromatography on silica gel in a 60% yield and 1:1.5 dr (determined by 1 H NMR analysis; major isomer) as a white solid.…”

“…The starting materials for the synthesis of 1 were prepared according to the literature [5,9]. Compound 4 was obtained following our previous work (3 × 20 mg scale).…”

“…Before this last report, we developed an organocatalytic cascade strategy for the diversification of thiopyranes utilizing trienamine activation. In this investigation, a tetrahydrocarboline scaffold (an analog of THC) could be incorporated into the final product 4, in a one-pot manner, with a good yield and excellent enantiomeric excess (Scheme 1b) [5].…”

Update on thiopyran-fused heterocycle synthesis (2013–2024)

“…The reac-tion was found to be quite general, and Scheme 39 gives a representative example. 60 The authors extended the methodology to construct indole-fused compounds by an intramolecular Pictet Spengler reaction in the presence of TFA at room temperature. Further, a double aminocatalytic cascade process was implemented using bis-dithioamide 206 and aldehyde 205, which led to the synthesis of a separable mixture of two diastereomers with 6 new stereocentres; the major diastereomer was obtained in 98% enantiomeric excess (Scheme 39).…”